Novel Venetoclax-Based Regimens in Patients With AML Unfit for Intensive Chemotherapy

A comprehensive review of novel venetoclax-based combination therapy in patients unfit for intensive chemotherapy who are diagnosed with AML.


Jorge E. Cortes, MD: Margie, before I go to the triplets, at ASH [American Society of Hematology Annual Meeting] we saw other venetoclax-based combinations that were arguably meant for unfit patients. There was low-dose cytarabine-cladribine-venetoclax and a CPX-351–venetoclax combination for unfit patients. Any thoughts about these combinations, these doublets, replacing azacitidine with something else? Do you think that has a role?

Margaret T. Kasner, MD:Let me let make 1 quick comment about azacitidine-IDH mutations because it fits here too.

Jorge E. Cortes, MD: Sure.

Margaret T. Kasner, MD:We have IDH-azacitidine vs placebo-azacitidine, but we don’t have IDH-azacitidine vs azacitidine-venetoclax, which we agree is our standard of care. All of this is what I try to teach my fellows not to do: comparing studies that don’t have anything to do with one another. That’s what’s happening with the combinations of venetoclax and other agents, like glasdegib or CPX-351. If we’re going to call azacitidine-venetoclax our standard of care for these older patients, and if we’re gaining the experience and becoming comfortable with treating patients in that setting, then until we have convincing data that that shouldn’t be the standard, none of these trials sways me. CPX-351–venetoclax is anything but lower intensity, and it depends on your patient population.

There are some promising early data that this may be a better combination in terms of outcomes for some subgroups of patients. Maybe this will be a little better for TP53-mutated patients than other combinations based on preliminary data, but it’s all very preliminary. There are very few patients in these studies. From a toxicity standpoint, you’re going to be talking about 7 days of venetoclax with something like CPX-351 for 14 days. And how much do people really need? In my mind, these ASH abstracts opened many interesting questions and areas for the future. I don’t think I’ll be incorporating them into my practice yet, although I’m curious to hear if Dr Carraway and Dr Jonas are considering.

Brian Andrew Jonas, MD, PhD: I’ll take the bait. No, I don’t think so. I agree with both of you. I’m still fairly entrenched in the azacitidine-venetoclax camp in terms of my main standard of care for older patients who are “unfit for chemotherapy.” With these escalated combos, like CPX-351–venetoclax, or Andrew Wei’s 5+2+venetoclax approach, and also the cladribine [plus] low-dose venetoclax, I wonder how they might compare the FLAG-IDA [fludarabine, cytarabine, idarubicin], which we discussed earlier as a potential frontline regimen. Could you go with something of a slightly higher intensity than azacitidine-venetoclax, but not quite as high intensity as full-intensity chemotherapy with venetoclax for some of these subpopulations?

Jorge E. Cortes, MD: We’re starting to get into a definition of unfit, and you have meet that to get this kind of chemotherapy. I see Hetty raising her hand. As I give her the platform, let’s extend it to the triplets, because we’re talking about triplets and the unfit. Instead of comparing [chemotherapy] with azacitidine-venetoclax, we’re adding to it. Hetty, give me your thoughts on both topics.

Hetty E. Carraway, MD:I want to highlight that these single IDH inhibitors can be well tolerated. You need to be more patient, and responses do happen in older patients. The data are provocative and nice for some of our patients who otherwise wouldn’t be able to tolerate something like azacitidine-venetoclax. That’s an important piece to put on the table.

The other piece I want to add is that there are ongoing studies using IDH inhibition in combination with venetoclax only. I’m looking forward to seeing those data because then we’ll get the benefit of the BCL2 inhibition with IDH inhibition, and that’s something to keep in mind. We’re all eagerly awaiting and interested in those data. Do you even need azacitidine in that setting?

That launches us into the triplet zone. Do we need all 3, or are there other agents out there? Margie mentioned the azacitidine-venetoclax-gilteritinib work, and that combination has been exciting. She highlighted that patients with FLT3-mutated AML [acute myeloid leukemia] are exposed to azacitidine-venetoclax-gilteritinib. In that study, azacitidine is 7 days, and gilteritinib and venetoclax are both 28 days; they get a day 14 marrow [test]. If that shows aplasia, then venetoclax and gilteritinib can be held, and patients can resume on cycle 2 with count recovery. They’re finding that patients have nice responses. A majority of patients are in remission with that triplet therapy. The challenges of that therapy are the cytopenias, as we talked about. But if we lead with modifying that dose with the right timeline, then that’s plausible, and we have very nice disease control.

The question then remains: do you need all 3, or can you get away with gilteritinib-venetoclax or gilteritinib-azacitidine? Those questions remain because you have added toxicity. The more agents you have, the more toxicity you have. Those are some of the questions we can’t answer today, but there are very exciting results if you’re able to dose-modify appropriately for the patients receiving that triplet combination.

I don’t know if others have comments or thoughts regarding triplets. Certainly, we’ll see other oral combinations, like the oral decitabine agent, ASTX727, plus venetoclax and an IDH inhibitor. That type of triplet therapy is undergoing early investigation. I think there were 30 patients in the study presented at ASH. Median follow-up is still less than 6 months, so it’s early for that triplet combination. We’re going to run into issues with toxicity and how best to modify that. Mediating those toxicities will be challenging, especially because not a huge number of patients are on the study in the de novo and relapsed/refractory settings.

We’re in the early days with this. We’re excited, and I’m going to tip my hat to your earlier comment about FLT3 inhibition. Adding that to what we have is our standard of care. It’s still not hitting the mark. It’s still not good enough. That’s why you’re seeing the community push to triplet therapy—to improve outcomes for our patients and to push the degree of toxicity that’s allowable so we can have added benefit. That’s where we are.

Jorge E. Cortes, MD: You mentioned earlier the gilteritinib-azacitidine combination. Although we haven’t seen the full data, the press release showed that the azacitidine-gilteritinib vs azacitidine alone was a negative study, which is a surprise. I was expecting that to be a positive study. It will be interesting to see the full data. Before we move to the next section, 1 of the attractive things about the triplet is if they eventually start replacing the 7+3 approach and getting into younger, fitter patients, because they’re going to be more intensive and have more toxicities. If you have very targeted agents—a FLT3 inhibitor, an IDH inhibitor, at some point maybe magrolimab—that could be a better way of managing these patients. They’re very intensive [in terms of] myelosuppression but perhaps less in terms of cardiotoxicity and mucositis. Maybe that’s the way to go.

Transcript edited for clarity.

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